Associations of salivary aldosterone levels during pregnancy with maternal blood pressure and birth weight-for-gestational age in a Mexico City birth cohort.

OBJECTIVE: To determine associations of maternal salivary aldosterone with blood pressure (BP) in pregnancy and infant birth weight-for-gestational age (BWGA). METHODS: We measured maternal salivary aldosterone, BP and BWGA z-scores in 471 Mexico City pregnancy cohort participants and performed multivariable linear regression of BP and BWGA on log-aldosterone levels. RESULTS: Log-aldosterone was positively associated with diastolic BP (ß = 0.12 95% CI: 0.04, 0.21). There were no main effects of log-aldosterone on BWGA. However, we detected an interaction between log-aldosterone and BP in association with BWGA; higher log-aldosterone was associated with lower BWGA in the lowest (ß = -0.12, 95% CI: -0.26, 0.02) and highest (ß = -0.12, 95% CI: -0.29, 0.06) BP tertiles. In contrast, in the middle BP tertile the association was positive (ß = 0.09, 95% CI: -0.02, 0.20), p for interaction = 0.03. CONCLUSION: Higher maternal salivary aldosterone is positively associated with diastolic BP and may affect fetal growth differently depending on concurrent maternal blood pressure.

Breastfeeding Duration and Cardiometabolic Health during Adolescence: A Longitudinal Analysis.

OBJECTIVE: To investigate the longitudinal association between breastfeeding duration and cardiometabolic health, using repeated measures study design among children and adolescents. STUDY DESIGN: This study included 634 offsprings aged 10 to 21 years (52% female) from the Early Life Exposure in Mexico to Environmental Toxicants birth cohort followed up to four time points during adolescence. Breastfeeding duration was prospectively quantified using questionnaires during early childhood. Cardiometabolic risk factors, body composition, and weight-related biomarkers were assessed as outcomes during adolescent follow-up visits. Sex-stratified linear mixed-effects models were used to model the association between quartiles of breastfeeding duration and outcomes, adjusting for age and additional covariates. RESULTS: Median breastfeeding duration was 7 months (minimum = 0, maximum = 36). Boys in the second quartile (median breastfeeding = 5 months) had lower total fat mass % (ß (SE) -3.2 (1.5) P = .037), and higher lean mass % (3.1 (1.6) P = .049) and skeletal muscle mass % (1.8 (0.8) P = .031) compared with the reference group (median breastfeeding = 2 months). A positive linear trend between breastfeeding duration and trunk lean mass % (0.1 (0.04) P = .035) was found among girls. No association was found with other cardiometabolic indicators. CONCLUSION: Despite sex-specific associations of breastfeeding duration with body composition, there was a lack of substantial evidence for the protective effects of breastfeeding against impaired cardiometabolic health during adolescence among Mexican youth. Further longitudinal studies with a robust assessment of breastfeeding are recommended.

Associations between blood leukocyte DNA methylation and sustained attention in mid-to-late childhood.

Aims: To identify associations between DNA methylation (DNAm) across the epigenome and symptoms related to attention-deficit/hyperactivity disorder in a population of Hispanic children. Materials & methods: Among 517 participants in the ELEMENT study aged 9-18 years, we conducted an epigenome-wide association study examining associations between blood leukocyte DNAm and performance on the Conners' continuous performance test (CPT3). Results: DNAm at loci in or near ZNF814, ELF4 and OR6K6 and functional enrichment for gene pathways pertaining to ferroptosis, inflammation, immune response and neurotransmission were significantly related to CPT3 scores. Conclusion: DNAm was associated with CPT3 performance. Further analysis is warranted to understand how these genes and enriched pathways contribute to attention-deficit/hyperactivity disorder.

Early Lead Exposure Associated with Molar Hypomineralization.

Purpose: The purpose of this study was to determine the association between prenatal and early life exposure to lead and the presence of molar hypomineralization (MH) in a group of Mexican children. Methods: A subset of participants of the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENTS) cohort study was examined for the presence of molar hypomineralization using European Academy of Pedi- atric Dentistry (EAPD) criteria. Prenatal lead exposure was assessed by K-ray fluorescence measurements of patella and tibia lead and by maternal blood lead levels by trimester and averaged over trimesters. Postnatal exposure was assessed by levels of maternal blood lead at delivery and child blood lead at 12 and 24 months. Results: A subset of 506 subjects from the ELEMENT cohorts (nine to 18 years old) were examined for MH; 87 subjects (17.2 percent) had MH. Maternal blood lead levels in the third trimester (odds ratio [OR] equals 1.08; 95 percent confidence interval [95% CI] equals 1.02 to 1.15) and averaged over three trimesters (OR equals 1.10; 95% CI equals 1.02 to 1.19) were significantly associated with MH status. None of the maternal bone lead or the child's blood lead parameters was significantly associated with the presence of MH (P>0.05). Conclusions: This study documents a significant association between prenatal lead exposure especially in late pregnancy and the odds of molar hypomineralization.

Associations between early-life exposure to PM2.5 and reductions in childhood lung function in two North American longitudinal pregnancy cohort studies.

Data integration of epidemiologic studies across different geographic regions can provide enhanced exposure contrast and statistical power to examine adverse respiratory effects of early-life exposure to particulate matter <2.5 microns in diameter (PM2.5). Methodological tools improve our ability to combine data while more fully accounting for study heterogeneity. Methods: Analyses included children enrolled in two longitudinal birth cohorts in Boston, Massachusetts, and Mexico City. Propensity score matching using the 1:3 nearest neighbor with caliper method was used. Residential PM2.5 exposure was estimated from 2 months before birth to age 6 years using a validated satellite-based spatiotemporal model. Lung function was tested at ages 6-11 years and age, height, race, and sex adjusted z scores were estimated for FEV1, FVC, FEF25-75%, and FEV1/FVC. Using distributed lag nonlinear models, we examined associations between monthly averaged PM2.5 levels and lung function outcomes adjusted for covariates, in unmatched and matched pooled samples. Results: In the matched pooled sample, PM2.5 exposure between postnatal months 35-44 and 35-52 was associated with lower FEV1 and FVC z scores, respectively. A 5 µg/m3 increase in PM2.5 was associated with a reduction in FEV1 z score of 0.13 (95% CI = -0.26, -0.01) and a reduction in FVC z score of 0.13 (95% CI = -0.25, -0.01). Additionally PM2.5 during postnatal months 23-39 was associated with a reduction in FEF25-75% z score of 0.31 (95% CI = -0.57, -0.05). Conclusions: Methodological tools enhanced our ability to combine multisite data while accounting for study heterogeneity. Ambient PM2.5 exposure in early childhood was associated with lung function reductions in middle childhood.

Is adiposity related to repeat measures of blood leukocyte DNA methylation across childhood and adolescence?

Epigenetic modifications such as DNA methylation may influence gene expression and phenotypes, including obesity in childhood. The directionality of this relationship is nevertheless unclear, and some evidence suggests that adiposity modifies the epigenome, rather than the other way around. In this pilot study, we utilize data from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study to examine whether measures of adiposity in childhood and early adolescence are associated with repeated measures of blood leukocyte DNA methylation at LINE-1 repetitive elements and two genes implicated in growth and adiposity: H19 and HSD11B2. Longitudinal epigenetic data were generated from cord blood and blood from follow-up visits in early and late adolescence. We assessed interactions between age and measures of body mass index (BMI) at 5 years of age and weight, BMI and waist circumference in early adolescence to infer whether adiposity deflects age-related DNA methylation changes throughout childhood. Applying linear mixed-effects models, we found an inverse association between measures of childhood BMI (kg/m2 ) and early-teen weight (kg) with repeat measures of H19 DNA methylation. We did not observe any statistically significant associations (p-value <.05) between any anthropometric measures and DNA methylation at LINE-1 or HSD11B2. We did not demonstrate statistically significant evidence in support of deflection of age-related DNA methylation trajectories by adiposity-related measures (age by adiposity interaction term). Given the pilot nature of this study, the relationships between repeat measures of DNA methylation and adiposity-measures across childhood merit further exploration in larger study populations.

Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements.

BACKGROUND: Lead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AIM: To assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. METHODS: We measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. RESULTS: Mothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DISCUSSION: Weekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Trimester-specific phthalate exposures in pregnancy are associated with circulating metabolites in children.

BACKGROUND: Prenatal phthalates exposures have been related to adiposity in peripuberty in a sex-specific fashion. Untargeted metabolomics analysis to assess circulating metabolites offers the potential to characterize biochemical pathways by which early life exposures influence the development of cardiometabolic risk during childhood and adolescence, prior to becoming evident in clinical markers. METHODS: Among mother-child dyads from the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) birth cohort, we measured 9 phthalate metabolites and bisphenol A in maternal spot urine samples obtained during each trimester of pregnancy, corrected for urinary specific gravity and natural log-transformed. In 110 boys and 124 girls aged 8-14 years, we used a mass-spectrometry based untargeted metabolomics platform to measure fasting serum metabolites, yielding 572 annotated metabolites. We estimated the associations between trimester-specific urinary toxicants and each serum metabolite, among all children or stratified by sex and adjusting for child age, BMI z-score, and pubertal onset. We accounted for multiple comparisons using a 10% false discovery rate (q<0.1). RESULTS: Associations between exposures and metabolites were observed among all children and in sex-stratified analyses (q<0.1). First trimester MEP, MiBP, and MCPP were associated with decreased 2-deoxy-D-glucose among all children. Among girls, third trimester concentrations of MECPP, MEHHP, MEHP, and MCPP were associated with 15, 13, 1, and 10 metabolites, respectively, including decreased choline and increased acylcarnitines and saturated FAs (FA). Among boys, third trimester MIBP was positively associated with 9 features including long chain saturated FAs, and second trimester MBzP was inversely associated with thyroxine. CONCLUSIONS: Metabolomics biomarkers may reflect sex- and exposure timing-specific responses to prenatal phthalate exposures manifesting in childhood that may not be detected using standard clinical markers of cardiometabolic risk.

Maternal urinary fluoride during pregnancy and birth weight and length: Results from ELEMENT cohort study.

Epidemiological studies assessing prenatal fluoride exposure and anthropometry at birth are scarce, inconsistent and with methodological limitations. The aim of this study was to evaluate associations between maternal urinary fluoride (MUF) at each trimester of pregnancy and birth weight and length in 536 mother-child pairs in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort study. MUF (mg/L) was measured using microdiffusion/fluoride-specific electrode from at least one trimester of pregnancy. Non-linear associations were assessed through segmented regression models (MUF and birth weight Z-score) and we used linear regression models for MUF and birth length Z-score. Models were adjusted for potential confounders including urinary creatinine concentrations as a covariate. Non-creatinine adjusted MUF levels at each trimester of pregnancy were 0.81, 0.86, and 0.82 mg/L, mean concentrations for first, second and third trimester, respectively. For birth weight, we identified a MUF breakpoint at 0.99, 0.68 and 0.58 mg/L, for first, second and third trimester of pregnancy, respectively. In the first trimester, an increase of 1 mg/L in MUF concentrations ≥0.99 mg/L was associated with an increase in weight Z-score at birth (ß = 0.79; 95% CI: 0.10, 1.48; p = 0.02). Second trimester MUF (≥0.68 mg/L) was marginally associated with birth weight decrease (ß = -0.25; 95% CI: -0.55, 0.04; p = 0.09) and third trimester MUF (≥0.58 mg/L) was significantly associated with birth weight decrease (ß = -0.33; 95% CI: -0.63, -0.03; p = 0.03). We observed a linear and significant association between MUF and Z-score of length at birth only for the first trimester of pregnancy (ß = 0.55; 95% CI: 0.07, 1.04; p < 0.02). Prenatal fluoride exposure was associated with birthweight z-score with different susceptibility windows. Our findings reinforce the hypothesis that maternal fluoride exposure may affect birth anthropometry.

Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort.

OBJECTIVE: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. METHODS: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children's IQ. All models controlled for relevant available covariates. RESULTS: The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed. CONCLUSION: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.

Third-Trimester Maternal Dietary Patterns Are Associated with Sleep Health among Adolescent Offspring in a Mexico City Cohort.

BACKGROUND: Maternal diet during gestation has been linked to infant sleep; whether associations persist through adolescence is unknown. OBJECTIVES: We explored associations between trimester-specific maternal diet patterns and measures of sleep health among adolescent offspring in a Mexico City birth cohort. METHODS: Data from 310 mother-adolescent dyads were analyzed. Maternal diet patterns were identified by principal component analysis derived from FFQs collected during each trimester of pregnancy. Sleep duration, midpoint, and fragmentation were obtained from 7-d actigraphy data when adolescents were between 12 and 20 y old. Unstratified and sex-stratified association analyses were conducted using linear regression models, adjusted for potential confounders. RESULTS: Mean ± SD age of offspring was 15.1 ± 1.9 y, and 52.3% of the sample was female. Three diet patterns were identified during each trimester of pregnancy: the Prudent Diet (PD), high in lean proteins and vegetables; the Transitioning Mexican Diet (TMD), high in westernized foods; and the High Meat & Fat Diet (HMFD), high in meats and fat products. Mean ± SD sleep duration was 8.5 ± 1.5 h/night. Most associations were found in the third trimester. Specifically, PD maternal adherence was associated with shorter sleep duration among offspring (-0.57 h; 95% CI: -0.98, -0.16 h, in the highest tertile compared with the lowest) and earlier sleep midpoint among females (-0.77 h; 95% CI: -1.3, -0.26 h). Adherence to the HMFD and TMD was nonlinearly associated with less fragmented sleep, with the latter only evident among females. CONCLUSIONS: Findings indicate that maternal dietary patterns, especially during the third trimester of pregnancy, may have long-term impacts on offspring sleep.

Dietary Influences on Urinary Fluoride over the Course of Pregnancy and at One-Year Postpartum.

Dietary factors are known to influence urinary fluoride (UF) levels in nonpregnant people. Maternal UF is used as a biomarker of fluoride exposure; however, dietary influences on UF during pregnancy are unknown. We compared UF levels and assessed the associations between UF and five select dietary influences in pregnancy vs. one-year postpartum: dietary fluoride (F), calcium intake from diet (Ca-diet), calcium intake from supplements (Ca-sup), dietary acid load (AL), and table salt use (TS) in 421 women exposed to fluoridated salt in the Mexican diet. Spot UF (mg/L) was measured by microdiffusion/fluoride-specific electrode and dilution-corrected with specific gravity (SG). Dietary variables were estimated from a validated Food Frequency Questionnaire. Comparisons among UF in pregnancy vs. one-year postpartum were performed with non-parametric tests. Associations between dietary variables and UF were assessed using random effect models (for pregnancy) and linear regression (for one-year postpartum). SG-corrected UF (median, range) during pregnancy (0.77, 0.01-4.73 mg/L) did not significantly differ from one-year postpartum (0.75, 0.15-2.62 mg/L) but did increase every 10 gestational weeks, ß = 0.05 (CI: 0.00-0.10). Different dietary influences on UF were identified at each state. Although Ca-diet and AL were not associated with UF in either state, Ca-sup decreased UF only during pregnancy, ß = - 0.012 mg/L (CI: - 0.023-0.00). Reporting TS use was associated with 12% increase in UF only at one-year postpartum (p = 0.026). These results suggest different dietary influences on UF in the pregnant state, which need consideration when using UF as a biomarker of fluoride exposure.

Prenatal lead exposure and childhood lung function: Influence of maternal cortisol and child sex.

INTRODUCTION: Maternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. MATERIALS AND METHODS: Analyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8-11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. RESULTS: A higher (flatter) diurnal slope was associated with lower FEV1/FVC ratio (ß: 0.433, 95%CI [-0.766, -0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV1/FVC and FEF25-75% (pinteraction<0.05 for all). Higher prenatal Pb was associated with reduced FEV1/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV1/FVC and FEF25-75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV1/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV1/FVC ratios (pinteraction = 0.067). CONCLUSIONS: Associations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.

Prenatal maternal pesticide exposure in relation to sleep health of offspring during adolescence.

STUDY OBJECTIVES: The neurobiological processes involved in establishing sleep regulation are vulnerable to environmental exposures as early as seven weeks of gestation. Studies have linked in utero pesticide exposure to childhood sleep-disordered breathing. However, the impact of in utero pesticide exposure on the sleep health of adolescents remains unexplored. MATERIALS AND METHODS: Data from 137 mother-adolescent pairs from a Mexico City cohort were analyzed. We used maternal urinary 3-phenoxybenzoic acid (3-PBA, pyrethroid metabolite) and 3, 5, 6-trichloro-2-pyridinol (TCPy, chlorpyrifos metabolite) from trimester three to estimate in utero pesticide exposure. Among adolescents, we obtained repeated measures of objectively assessed sleep duration, midpoint, and fragmentation using wrist-actigraphy devices for 7 consecutive days in 2015 and 2017. Unstratified and sex-stratified associations between maternal urinary 3-PBA and TCPy and adolescent sleep measures were examined using generalized linear mixed models (GLMMs). We also examined the interactive effects of maternal pesticide exposure and offspring sex on sleep outcomes. RESULTS: 3-PBA and TCPy were detected in 44.4% and 93% of urine samples, respectively. Adjusted findings demonstrated that higher exposure to maternal TCPy was associated with longer sleep duration and later sleep timing. Findings from interaction tests between maternal pesticide exposure and offspring sex were not statistically significant, although adjusted sex-stratified findings showed that the association between TCPy with duration and midpoint was evident only among female offspring. To illustrate, those in the highest tertile of exposure had a 59 minute (95% CI: 12.2, 104.8) (p, trend = 0.004) longer sleep duration and a 0.6 hour (95% CI: 0.01, 1.3) (p, trend = 0.01) later sleep midpoint. We found no significant associations between 3-PBA and sleep outcomes. CONCLUSION: Within a cohort of mother-adolescent pairs, we found associations between maternal prenatal pesticide exposure and longer sleep duration and later sleep timing among adolescent offspring. Further, this association may be female-specific.

Maternal Phthalates Exposure and Blood Pressure during and after Pregnancy in the PROGRESS Study.

BACKGROUND: Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure. OBJECTIVES: We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum. METHODS: Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (n=892). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure. RESULTS: As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (ΣDEHP) were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum ("increase-increase") or decreased blood pressure through 18 months postpartum with a gradual increase thereafter ("decrease-increase"). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase-increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate (ΣDBP) biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for ΣDEHP, MECPTP, MBzP, and ΣDBP. DISCUSSION: In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562.

Prenatal and Early Childhood Exposure to Lead and Repeated Measures of Metabolic Syndrome Risk Indicators From Childhood to Preadolescence.

Background: Exposure to lead (Pb) during the early life stages has been associated with the development of metabolic syndrome (MetS). Longitudinal studies of Pb exposure in critical developmental windows in children are limited. Methods: Our study included 601 mother-child dyads from the PROGRESS (Programming Research in Obesity, Growth, Environment and Social Stressors) birth cohort. Blood lead levels (BLLs) were assessed during the second and third gestational trimesters, in cord blood at delivery, and at ages 1, 2, and 4 years. Bone lead levels in the patella and tibia were assessed at 1 month postpartum and evaluated in separate models. To account for cumulative exposure (prenatal, postnatal, and cumulative), we dichotomized the BLLs at each stage visit and determined the following: "higher" if a BLL was at least once above the median (HPb) and "lower" if all BLLs were below the median (LPb). We analyzed fasting glucose, HbA1c, triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (cHDL), low-density lipoprotein cholesterol (cLDL), body mass index, waist circumference (WC), body fat percentage, and systolic (SBP) and diastolic blood pressure (DBP) at two study visits between 6 and 12 years of age and created cutoff points based on the clinical guidelines for each indicator. Mixed effects models were used to analyze each outcome longitudinally for each BLL score, adjusting for child's sex, size for gestational age, child's age, maternal parity, mother's age, and socioeconomic status. Results: We observed associations for HPb exposure and TC in all stages (OR = 0.53, 95%CI = 0.32-0.86) and postnatally (OR = 0.59, 95%CI = 0.36-0.94) and for prenatal HPb and TGs (OR = 0.65, 95%CI = 0.44-0.95). HPb at all stages was associated with WC (OR = 0.27, 95%CI = 0.08-0.86), BMI (OR = 0.33, 95%CI = 0.11-0.99), SBP (OR = 0.53, 95%CI = 0.32-0.85), and DBP (OR = 0.57, 95%CI = 0.34-0.95). Pb levels in the patella were associated with cHDL (OR = 1.03, 95%CI = 1.00-1.07) and those in the tibia with TGs (OR = 0.95, 95%CI = 0.91-0.99). Conclusion: Early life exposure to Pb may alter early indicators of MetS. A follow-up of these children will allow for more definition on the impact of longer-term exposures.

Prenatal Lead (Pb) Exposure and Peripheral Blood DNA Methylation (5mC) and Hydroxymethylation (5hmC) in Mexican Adolescents from the ELEMENT Birth Cohort.

BACKGROUND: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles. OBJECTIVE: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11-18 years of age. METHODS: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n=144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction. RESULTS: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43±5.16µg/dL in Trimester 1 (T1), 5.66±5.21µg/dL in Trimester 2 (T2), and 5.86±4.34µg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean±standard deviation(SD), 2.08±4.18%), NINJ2 (G/C: 2.01±5.95; GG: 0.90±3.97), RAB5A (0.66±0.80%), and TPPP (1.11±6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3±9.63%), NINJ2 (heterozygotes: 38.6±7.39%; GG homozygotes: 67.3±9.83%), RAB5A (1.41±1.21%), and TPPP (92.5±8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (ß=-0.37, p=0.03) and 5hmC in NINJ2 (ß=0.49, p=0.003); T2 BLLs with 5mC in HCN2 (ß=0.37, p=0.03) and 5hmC in NINJ2 (ß=0.27, p=0.008); and T3 BLLs with 5mC in HCN2 (ß=0.50, p=0.01) and NINJ2 (ß=-0.35, p=0.004) and 5hmC in NINJ2 (ß=0.45, p<0.001). NINJ2 5mC was negatively correlated with gene expression (Pearson r=-0.5, p-value=0.005), whereas 5hmC was positively correlated (r=0.4, p-value=0.04). DISCUSSION: These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507.

Exposure to Phenols, Phthalates, and Parabens and Development of Metabolic Syndrome Among Mexican Women in Midlife.

Background: Evidence suggests exposure to endocrine-disrupting chemicals (EDCs) can influence Metabolic Syndrome (MetS) risk in adults, but it is unclear if EDCs impact women during midlife. We examined if EDCs measured in adult women were predictive of MetS and its components 9 years later. Methods: We measured urinary phthalate metabolites, phenols, and parabens collected in 2008 among 73 females from the ELEMENT study. MetS and its components (Abdominal Obesity, Hypertriglyceridemia, Cholesterolemia, Hypertension, and Hyperglycemia) were assessed in 2017. We regressed log-transformed EDC concentrations on MetS and MetS components using logistic regression, adjusting for age and physical activity. Results: At follow-up, the mean (SD) age was 46.6 (6.3) years; the prevalence of MetS was 34.3%. Sum of dibutyl phthalate metabolites (ΣDBP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP) were associated with an increased odds of hypertriglyceridemia. 2,5-dichlorophenol (2,5 DCP) and 2,4-dichlorophenol (2,4 DCP) were associated with increased odds of hypertriglyceridemia. The odds of hypertension were 4.18 (95% CI: 0.98, 17.7, p < 0.10) and 3.77 (95% CI: 0.76, 18.62, p < 0.10) times higher for every IQR increase in MCOP and propyl paraben, respectively. The odds of hyperglycemia were 0.46 (95% CI: 0.18, 1.17 p < 0.10) times lower for every IQR increase in the sum of di-2-ethylhexyl phthalate metabolites (ΣDEHP), and the odds of abdominal obesity were 0.70 (95% CI: 0.40, 1.21, p < 0.10) lower for every IQR increase in the concentration of triclosan. Conclusion: We found EDCs measured in 2008 were marginally predictive of hypertriglyceridemia and hypertension 9 years later. Results suggest that lower exposure to certain toxicants was related to lower markers of metabolic risk among midlife women.

Association between cumulative childhood blood lead exposure and hepatic steatosis in young Mexican adults.

BACKGROUND: Exposure to environmental toxicants may play a role in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD). Cumulative exposure to lead (Pb) has chronic and permanent effects on liver function. Pediatric populations are vulnerable to the toxic effects of Pb, even at low exposure levels. The purpose of the study was to estimate the association between cumulative Pb exposure during childhood and hepatic steatosis biomarkers in young Mexican adults. METHODS: A subsample of 93 participants from the ELEMENT cohort were included in this study. Childhood blood samples were collected annually from ages 1-4 years and were used to calculate the Cumulative Childhood Blood Lead Levels (CCBLL). Hepatic steatosis during adulthood was defined as an excessive accumulation of hepatic triglycerides (>5%) determined using Magnetic Resonance Imaging (MRI). Liver enzymes were also measured at this time, and elevated liver enzyme levels were defined as ALT (≥30 IU/L), AST (≥30 IU/L), and GGT (≥40 IU/L). Adjusted linear regression models were fit to examine the association between CCBLL (quartiles) and the hepatic steatosis in young adulthood. RESULTS: In adulthood, the mean age was 21.4 years, 55% were male. The overall prevalence of hepatic steatosis by MRI was 19%. Elevate levels of the enzymes ALT, AST, and GGT were present in 25%, 15%, and 17% of the sample, respectively. We found a positive association between the highest quartile of CCBLL with the steatosis biomarkers of hepatic triglycerides (Q4 vs. Q1: ß = 6.07, 95% CI: 1.91-10.21), elevated ALT (Q4 vs. Q1: ß = 14.5, 95% CI: 1.39-27.61) and elevated AST (Q4 vs. Q1: ß = 7.23, 95% CI: 0.64-13.82). No significant associations were found with GGT. CONCLUSIONS: Chronic Pb exposure during early childhood is associated with a higher levels of hepatic steatosis biomarkers and hepatocellular injury in young adulthood. More actions should be taken to eliminate sources of Pb during the first years of life.

Dietary fluoride intake over the course of pregnancy in Mexican women.

OBJECTIVE: To estimate dietary fluoride intake (F) over the course of pregnancy and the overall adjusted difference in dietary F intake by pregnancy stages and levels of compliance with dietary recommendations. DESIGN: Secondary data analysis from a longitudinal pregnancy cohort study in a population exposed to fluoridated salt. Women were followed during the early, middle and late stages of their pregnancy (n 568). The dietary intake of recommended prenatal nutrients according to Mexican dietary guidelines and F intake (mg/d) was estimated with a validated FFQ. Data were summarised with descriptive statistics. Levels of F intake were compared with the USA's Institute of Medicine adequate intake (AI) of 3 mg/d for pregnancy. Adjusted differences in F intake by pregnancy stages and levels of compliance with recommendations were estimated using random effects models. SETTING: Mexico City. PARTICIPANTS: Women participating in the Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) project, from 2001 to 2003. RESULTS: Median dietary F intake throughout pregnancy ranged from 0·64 (interquartile range (IQR) 0·38) in the early to 0·70 (IQR 0·42) in the middle, and 0·72 (IQR 0·44) mg/d in the late stage (0·01 mg F/kg per d). Corresponding adjusted intakes of F were 0·72 (95 % CI 0·70, 0·74), 0·76 (95 % CI 0·74, 0·77) and 0·80 (95 % CI 0·78, 0·82) mg/d. Women who were moderately and highly compliant with Mexican dietary recommendations ingested, on average, 0·04 and 0·14 mg F/d more than non-compliant women (P < 0·005). CONCLUSIONS: Dietary F intake was below current AI, was greater with the progression of pregnancy and in women who were moderately and highly compliant with dietary recommendations.